HK1153468A - Preparation of sulfamide derivatives - Google Patents

Description

Preparation of sulfamide derivatives

Technical Field

The present invention relates to a novel process for the preparation of sulfamide derivatives, which are useful in the treatment of epilepsy and related disorders.

Background

Epilepsy refers to a condition in which a person has periodic seizures due to a chronic, underlying process. Epilepsy refers to a clinical manifestation rather than a single disease, as there are many forms and causes of epilepsy. It is estimated that if epilepsy is used to define two or more unproductive seizures of the disease, the incidence of epilepsy in different populations around the world is approximately 0.3% to 0.5%, and the prevalence of epilepsy is estimated to be 5 to 10 per 1000 people.

An essential step in the evaluation and management of epileptic patients is the determination of the type of epilepsy that has occurred. The main feature that distinguishes between different types of epilepsy is whether the seizure is partial (synonymous with focal) or generalized.

Partial seizures are conditions in which seizures are confined to discrete areas of the cerebral cortex. If consciousness is fully conscious during a seizure and the clinical manifestations are considered relatively simple, it is called simple partial seizure epilepsy. If there is a disturbance in consciousness, it is called a complex partial seizure epilepsy. An important additional subtype includes the condition of partial seizures starting at the beginning and then spreading to the entire cortex, which is known as generalized seizures secondary to partial seizures.

Systemic attacks involve simultaneous diffusion to brain regions in a bilaterally symmetric fashion. Unconscious epilepsy or petit mal seizures are characterized by sudden, brief loss of consciousness without loss of posture control. Atypical absence epilepsy typically involves prolonged sustained loss of consciousness, less sudden onset and cessation, and more pronounced signs of motion that may include focal or lateral features. Generalized tonic clonic or grand mal seizures are the main type of generalized seizures characterized by sudden seizures with no precursor. The initial stages of epilepsy are often myotonic contractions, respiratory disorders, increased heart rate due to a significant increase in sympathetic tone, increased blood pressure and dilated pupils. After 10-20 seconds, the tonic phase of epilepsy usually evolves into clonic phases, which are formed by the superposition of muscle relaxation cycles to tonic muscle contraction cycles. The relaxation period gradually increases until the end of the attack period, which usually lasts no more than 1 minute. The post-onset phase is characterized by unresponsiveness, muscle relaxation, and excessive salivation (which can lead to wheezing breathing and local airway obstruction). Dystonic epilepsy is characterized by a sudden loss of postural muscle tone for 1-2 seconds. Consciousness is transiently impaired, but there is often no post-seizure confusion. Myoclonic epilepsy is characterized by sudden and transient muscle contractions, which may involve a part of the body or the whole body.

Mccosey, d, et al, in U.S. patent publication US2006/0041008a1, published 2006, 2/23, 2006, disclose sulfamide derivatives useful for the treatment of epilepsy and related disorders, and methods for the preparation of sulfamide. There remains a need for a process suitable for large scale preparation of starting materials for commercial preparation of sulfamide derivative compounds.

Disclosure of Invention

The present invention relates to a process for the preparation of a compound of formula (I-A) or a pharmaceutically acceptable salt thereof,

wherein

R¹And R²Each independently selected from hydrogen and lower alkyl;

a is an integer of 1 to 2;

is selected from

Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; and wherein each R⁵Are each independently selected from halogen, lower alkyl and nitro;

provided that when

Is composed of

If so, a is 1;

the method comprises the following steps:

reacting a compound of formula (X) (wherein Q)¹Is trifluoromethanesulfonic acid group) with a compound of formula (XI) (wherein PG is¹Is hydrogen or a nitrogen protecting group, and wherein M¹Hydrogen) in an organic solvent in the presence of a base to form the corresponding compound of formula (XII);

or a compound of formula (X) (wherein Q)¹Is trifluoromethanesulfonic acid group) with a compound of formula (XI) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Is a metal cation or a tertiary ammonium cation) in an organic solvent to form the corresponding compound of formula (XII).

Deprotecting the compound of formula (XII) to produce the corresponding compound of formula (I-A).

In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I-S),

also known as N- [ [ (2S) -6-chloro-2, 3-dihydro-1, 4-benzodioxan-2-yl ] methyl ] -sulfonamide;

the method comprises the following steps:

reacting a compound of formula (X-S) (wherein Q)¹Is trifluoromethanesulfonic group) with a compound of formula (XI-S) (wherein PG is¹Is hydrogen or a nitrogen protecting group, and wherein M¹Hydrogen) in an organic solvent in the presence of a base to form the corresponding compound of formula (XI I-S);

or a compound of formula (X-S) (wherein Q)¹Is trifluoromethanesulfonic group) with a compound of formula (XI-S) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Which is a metal cation or a tertiary ammonium cation) in an organic solvent to form the corresponding compound of formula (XII-S).

Deprotecting the compound of formula (XII-S) to produce the corresponding compound of formula (I-S).

The invention also relates to the preparation of compounds of formula (XII)

Wherein

PG¹Is hydrogen or a nitrogen protecting group (preferably, PG)¹Is tert-butyloxycarbonyl)

R¹And R²Each independently selected from hydrogen and lower alkyl;

a is an integer of 1 to 2;

is selected from

Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; and wherein each R⁵Are each independently selected from halogen, lower alkyl and nitro;

provided that when

Is composed of

When the value is 1, a is obtained.

In one embodiment, the invention relates to compounds of formula (XII-S),

wherein

PG¹Is hydrogen or a nitrogen protecting group (preferably, PG)¹Is tert-butoxycarbonyl). Compounds of formula (XI I) and compounds of formula (XI I-S) are useful as intermediates in the synthesis of compounds of formula (I-A) and compounds of formula (I-S), respectively.

The invention also relates to products prepared according to the methods described herein.

The present invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product made according to the methods described herein. The present invention illustrates a pharmaceutical composition made by mixing a product made according to the process described herein with a pharmaceutically acceptable carrier. The present invention illustrates a process for preparing a pharmaceutical composition comprising admixing a product prepared according to the process described herein and a pharmaceutically acceptable carrier.

The present invention is exemplified by a method of treating epilepsy and related disorders comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compounds described herein for the preparation of a medicament for treating epilepsy or a related disorder in a subject in need thereof.

Detailed Description

The invention relates to a method for producing compounds of formula (I-A) and compounds of formula (II-A),

wherein all substituents are as defined herein, and pharmaceutically acceptable salts thereof. The compounds of the invention are useful in the treatment of epilepsy and related disorders.

The invention also relates to compounds of the formula (XII),

wherein all substituents are as defined herein. The compounds of formula (XII) are useful as intermediates in the synthesis of compounds of formula (I-A). In one embodiment, the invention relates to compounds of formula (XII-S),

wherein all substituents are as defined herein, are useful as intermediates in the synthesis of compounds of formula (I-A). .

As used herein, the term "epilepsy and related disorders" or "epilepsy or related disorders" shall refer to any disorder in which a subject (preferably an adult, child or infant) experiences one or more seizures and/or tremors. Suitable examples include, but are not limited to, epilepsy (including, but not limited to, partial epilepsy, generalized epilepsy, epilepsy with both partial and generalized seizures, and the like), seizures as a complication of a disease or condition (e.g., seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug or withdrawal, alcohol or withdrawal, sleep deprivation, and the like), essential tremor, restless limb syndrome, and the like. Preferably, the disease is selected from epilepsy (regardless of type, root cause or cause), essential tremor or restless limb syndrome; more preferably, the disease is epilepsy (regardless of type, root cause or cause) or essential tremor.

In one embodiment of the present invention, PG¹Is hydrogen or a nitrogen protecting group. In another embodiment of the present invention, PG¹Is a nitrogen protecting group. In another embodiment of the present invention, PG¹Is hydrogen, BOC or Cbz. In another embodiment of the present invention, PG¹Is BOC or Cbz. In another embodiment of the present invention, PG¹Is hydrogen or BOC. In one embodiment of the present invention, PG¹Is BOC.

In one embodiment of the invention, R¹Selected from hydrogen and methyl. In another embodiment of the invention, R²Selected from hydrogen and methyl. In another embodiment of the invention, R¹And R²Each is hydrogen or R¹And R²Each is methyl.

In one embodiment of the invention, - (CH)₂)_a-is selected from-CH₂-and-CH₂-CH₂-. In another embodiment of the present invention, - (CH)₂)_ais-CH₂-。

In one embodiment of the invention, a is 1.

In one embodiment of the present invention, b is an integer of 0 to 2. In another embodiment of the present invention, c is an integer from 0 to 2. In another embodiment of the present invention, b is an integer of 0 to 1. In another embodiment of the present invention, c is an integer from 0 to 1. In another embodiment of the present invention, the sum of b and c is an integer of 0 to 2, preferably 0 to 1. In another embodiment of the present invention, b is an integer from 0 to 2, and c is 0.

In one embodiment of the present invention,

is a cyclic structure selected from

In a further embodiment of the present invention,

is a cyclic structure selected from

In one embodiment of the present invention,

is a cyclic structure selected from the group consisting of 2- (chromanyl), 2- (6-chloro-2, 3-dihydro-benzo [1, 4] dioxane, 2- (benzo [1, 3] dioxolanyl), 2- (5-chloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (7-nitro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (6, 7-dichloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (2, 3-dihydro-naphtho [2, 3-b ] [1, 4] dioxane, and 2- (7-chloro-benzo [1, 3] dioxolanyl). In a further embodiment of the present invention,

is a cyclic structure selected from the group consisting of 2- (5-chloro-2, 3-dihydro-benzo [1, 4] dioxane yl), 2- (7-nitro-2, 3-dihydro-benzo [1, 4] dioxane yl), 2- (6, 7-dichloro-2, 3-dihydro-benzo [1, 4] dioxane yl), and 2- (2, 3-dihydro-naphtho [2, 3-b ] [1, 4] dioxane yl).

In one embodiment of the present invention,

is selected from

In a further embodiment of the present invention,

is selected from

In one embodiment of the present invention,

selected from the group consisting of 2- (2, 3-dihydro-benzo [1, 4] dioxane), 2- (benzo [1, 3] dioxolanyl), 3- (3, 4-dihydro-benzo [1, 4] dioxepin), 2- (6-chloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (6-fluoro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (chromanyl), 2- (5-fluoro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (7-chloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (6-chloro-benzo [1, 4] dioxane, 3] dioxolanyl), 2- (7-nitro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (7-methyl-2, 3-dihydro-benzo [1, 4] dioxane), 2- (5-chloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (6-bromo-2, 3-dihydro-benzo [1, 4] dioxane), 2- (6, 7-dichloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (8-chloro-2, 3-dihydro-benzo [1, 4] dioxane), 2- (2, 3-dihydro-naphtho [2, 3-b ] [1, 4] dioxane group) and 2- (4-methyl-benzo [1, 3] dioxopentacyl) group.

In a further embodiment of the present invention,

selected from the group consisting of 2- (benzo [1, 3] dioxopentacyl), 2- (2, 3-dihydro-benzo [1, 4] dioxanyl), 2- (6-chloro-2, 3-dihydro-benzo [1, 4] dioxanyl), 2- (7-methyl-2, 3-dihydro-benzo [1, 4] dioxanyl), 2- (6-bromo-2, 3-dihydro-benzo [1, 4] dioxanyl), and 2- (6, 7-dichloro-2, 3-dihydro-benzo [1, 4] dioxanyl). In a further embodiment of the present invention,

selected from 2- (2, 3-dihydro-benzo [1, 4] dioxane yl), 2- (7-methyl-2, 3-dihydro-benzo [1, 4] dioxane yl) and 2- (6-bromo-2, 3-dihydro-benzo [1, 4] dioxane yl).

In one embodiment of the invention, R⁵Selected from (I I) halogen and lower alkyl. In another embodiment of the present invention, R⁵Selected from chlorine, fluorine, bromine and methyl.

In one embodiment of the invention, the stereocenter of the compound of formula (I-A) is in the S configuration. In another embodiment of the invention, the stereocenter of the compound of formula (I-A) is in the R-configuration.

In one embodiment of the invention, the compound of formula (I-A) is present as an enriched enantiomeric mixture wherein the% enantiomeric enrichment (% ee) is greater than about 75%, preferably greater than about 90%, more preferably greater than about 95%, and most preferably greater than about 98%.

Additional embodiments of the invention include those in which a substituent is selected for one or more of the variables defined herein (i.e., R)¹、R²、R⁵A, b, etc.) are independently selected as any individual substituent or any subset of substituents selected from the entire list as defined herein. In another embodiment of the present invention, a method of making any single compound or subset of compounds selected from the representative compounds listed in table 1 below is shown.

Wherein stereocenters are present in the compounds listed in table 1 below, the compounds are prepared as mixtures of stereoconfigurations, unless otherwise indicated. In the case where a stereogenic center is present, the designations S and R in the "stereoconfiguration" column are intended to indicate that the exact stereoconfiguration of the center has not been determined.

Table 1: representative compounds of formula (I-A)

As used herein, the term "halogen" shall refer to chlorine, bromine, fluorine and iodine, unless otherwise indicated.

As used herein, unless otherwise indicated, the term "alkyl", whether used alone or as part of a substituent group, includes straight and branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like. Unless otherwise indicated, "lower" and as used in reference to alkyl refers to carbon chain compositions having 1 to 4 carbon atoms.

As used herein, unless otherwise indicated, "alkoxy" shall mean an oxygen ether group of a straight or branched chain alkyl group as described above. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy and the like.

When a particular group is "substituted" (e.g., alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), the group can have one or more substituents, preferably 1 to 5 substituents, more preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, each independently selected from the list of substituents.

The term "independently" with respect to a substituent means that when there may be more than one such substituent, the substituents may be the same or different from each other.

As used herein, a "+" designation indicates the presence of a stereocenter.

In the case where the compounds according to the invention have at least one chiral center, they may therefore be present in enantiomeric form. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, that enantiomer is present in an enantiomeric excess of greater than or equal to about 80%, more preferably, in an enantiomeric excess of greater than or equal to about 90%, even more preferably, in an enantiomeric excess of greater than or equal to about 95%, even more preferably, in an enantiomeric excess of greater than or equal to about 98%, and most preferably, in an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present in greater than or equal to about 80% diastereomeric excess, more preferably, in greater than or equal to about 90% diastereomeric excess, even more preferably, in greater than or equal to about 95% diastereomeric excess, even more preferably, in greater than or equal to about 98% diastereomeric excess, and most preferably, in greater than or equal to about 99% enantiomeric excess.

Furthermore, certain crystal forms of the compounds of the present invention may exist as polymorphs and as such are intended to be included within the scope of the present invention. Moreover, certain compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be included within the scope of the present invention.

Under standard nomenclature used throughout the specification, the terminal portion of the designated side chain is described first, followed by a description of the functional group adjacent to the point of attachment. Thus, for example, a "phenylalkylaminocarbonylalkyl" substituent refers to a group of the formula:

abbreviations used in this specification, particularly in the "schemes" and "examples", are as follows:

aq.	＝	aqueous solution
			conc.	＝	Is concentrated
Cbz or CBz	＝	Benzyloxycarbonyl group
			DIPEA	＝	Diisopropylethylamine

DMF	＝	N, N-dimethylformamide
			DMSO	＝	Dimethyl sulfoxide
Et3N or TEA	＝	Triethylamine
			EtOAc	＝	Ethyl acetate
IPA	＝	Isopropanol (I-propanol)
			MeOH	＝	Methanol
NMM	＝	N-methylmorpholine (also known as 4-methylmorpholine)
			satd.	＝	Saturated
t-BOC or Boc	＝	Tert-butoxycarbonyl group
			TEA	＝	Triethylamine
TFA	＝	Trifluoroacetic acid
			TLC	＝	Thin layer chromatography
Triflate	＝	Trifluoromethanesulfonic acid anion, also known as trifluoromethanesulfonic acid group

As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separate from any mixture, solvent system, or biological environment formed with another compound. In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I-A), preferably a compound of formula (I-S), in isolated form.

As used herein, unless otherwise indicated, the term "substantially pure compound" shall mean that the mole percentage of impurities in the isolated compound is less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, most preferably less than about 0.1 mole%. In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I-A), preferably a compound of formula (I-S), which can be prepared as a substantially pure compound.

As used herein, unless otherwise indicated, the term "substantially free of corresponding salt forms" when used to describe a compound of formula (I) shall mean that the mole percentage of any corresponding salt form in the isolated compound is less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, most preferably less than about 0.1 mole%. In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I-a), preferably a compound of formula (I-S), which can be prepared in the form of a compound substantially free of the corresponding salt form.

As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

One skilled in the art will recognize that the reaction steps, if not otherwise indicated, are carried out according to known methods under suitable conditions to provide the desired product.

One skilled in the art will recognize in the description and claims presented herein that where a reagent or class/type of reagent (e.g., base, solvent, etc.) is recited in more than one step of a method, then each reaction step is independently selected for each reagent, and each reagent may be the same or different from each other. For example, where two steps of the process recite an organic or inorganic base as a reagent, then the organic or inorganic base selected for the first step can be the same or different from the organic or inorganic base of the second step.

In order to provide a more concise description, certain quantitative representations given herein are not intended to be limited by the term "about". It is to be understood that each quantity given herein is intended to refer to the actual given value, and it is also intended to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given value, whether or not the term "about" is explicitly used.

As used herein, unless otherwise indicated, the term "aprotic solvent" shall refer to any solvent that does not produce protons. Suitable examples include, but are not limited to, DMF, 1, 4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.

As used herein, unless otherwise specified, the term "leaving group" shall mean a charged or uncharged atom or group that is liberated during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, triflate, and the like.

As used herein, unless otherwise indicated, the term "nitrogen protecting group" shall mean a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in a reaction and that can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamates, i.e., groups of the formula-C (O) O-R, wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenethyl, CH₂＝CH-CH₂-and the like; amides, i.e., groups of formula-C (O) -R ', wherein R' is, for example, methyl, phenyl, trifluoromethyl, and the like; n-sulfonyl derivatives, i.e. of formula-SO₂A group of-R ', wherein R' is, for example, tolyl, phenyl, trifluoromethyl, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-yl, 2, 3, 6-trimethyl-4-methoxyphenyl, or the like; other suitable nitrogen protecting groups may be found, for example, in t.w. greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley&Sons, 1991(T.W.Greene and P.G.M.Wuts, "protecting groups in organic Synthesis, John Wiley&Sons, 1991).

One skilled in the art will recognize that if the reaction step of the present invention can be carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems.

If the process for preparing the compounds according to the invention yields mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or the individual enantiomers may be prepared by enantiospecific synthesis or by resolution. The compounds may be resolved, for example, into their component enantiomers by standard techniques, e.g., by salt formation with an optically active acid (e.g., (-) -di-p-toluoyl-D-tartaric acid and/or (+) -di-p-toluoyl-L-tartaric acid) to form diastereomeric pairs, followed by fractional crystallization and re-generation of the free base. The compounds may also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by conventional protecting groups, for example inProtective Groups in Organic ChemistryMcOmie, Plenum Press, 1973 (protective groups in organic chemistry, J.F.W.McOmie, Plenum Press, 1973); and t.w.greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley&Sons, 1991(T.W.Greene and P.G.M.Wuts, "protecting groups in organic Synthesis, John Wiley&Sons, 1991). The protecting group may be removed at a convenient subsequent stage by methods known in the art.

For use in medicine, a salt of a compound of the invention refers to a non-toxic "pharmaceutically acceptable salt". However, other salts may be used to prepare the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric, sulfuric, fumaric, maleic, succinic, acetic, benzoic, citric, tartaric, carbonic or phosphoric acid. In addition, if the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts with suitable organic ligands (e.g., quaternary ammonium salts). Thus, representative pharmaceutically acceptable salts include the following salts:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, laurylsulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinol, hydrabamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (pamoate), Palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, 1, 8-chlorotheyl salt, tosylate, triethyliodide, and valerate.

Representative acids and bases for preparing pharmaceutically acceptable salts include the following:

acids, including acetic acid, 2-dichloroacetic acid, acetylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) -L-lactic acid, and mixtures thereof, (±) -DL-lactic acid, lactobionic acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfinic acid and undecylenic acid; and

bases, including ammonia, L-arginine, benzphetamine, benzathine, calcium hydroxide, choline, dandol, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, cholamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

The present invention relates to a process for the preparation of compounds of formula (I-a), as described in more detail in scheme 1 below:

scheme 1

An appropriately substituted compound of formula (X) (wherein Q) according to the above figure¹Is a trifluoromethanesulfonic group, a known compound or compound prepared by known methods) with an appropriately substituted compound of formula (XI) in which PG is¹Hydrogen or a suitably selected nitrogen protecting group, e.g. Boc, Cbz, etc., preferably Boc; and wherein M¹Hydrogen) in the presence of a base, examples of bases are: such as K₂CO₃、Na、Cs₂CO₃Etc. (preferably K)₂CO₃) An inorganic base of (a); or tertiary ammonium bases such as NMM, TEA, DIPEA, pyridine, and the like; wherein the base is preferably present in an amount ranging from about 1.0 to about 5.0 molar equivalents, preferably from about 4.0 to 5.0 molar equivalents; the reaction is carried out in an organic solvent such as toluene, acetone, DMF, etc.; preferably in a polar aprotic solvent, such as acetone, DMF, 2-butanol, and the like, preferably acetone; provided that the compound of formula (X) and the compound of formula (XI) are soluble in the selected organic solvent; the reaction produces the corresponding compound of formula (XII).

Alternatively, a compound of formula (X) (which isMiddle Q¹Is trifluoromethanesulfonic acid group) with an appropriately substituted compound of formula (XI) in which PG is¹Is a nitrogen protecting group such as Boc, Cbz, etc., preferably BOC; and wherein M¹Is a metal cation, e.g. sodium cation (Na)⁺) Potassium cation (K)⁺) Etc.; or a tertiary ammonium cation, such as an N-methylmorpholine cation, a trialkylammonium cation (e.g., triethylammonium cation), etc., preferably an N-methylmorpholine cation) in an organic solvent such as toluene, acetone, DMF, etc.; preferably in a polar aprotic solvent, such as acetone, DMF, 2-butanol, and the like, preferably acetone; provided that the compound of formula (X) and the compound of formula (XI) are soluble in the selected organic solvent; the reaction produces the corresponding compound of formula (XII).

The compound of formula (XII) is deprotected according to known methods to give the corresponding compound of formula (I-A). For example, PG in which a compound of formula (XII)¹In the case of BOC, the compound of formula (XII) is reacted with an appropriately selected acid (e.g., HCl (e.g., aqueous HCl), TFA, etc.) in an organic solvent (e.g., methanol, ethanol, IPA, etc.) to deprotect the compound of formula (XII) to produce the corresponding compound of formula (I-A).

Preferably, the compound of formula (I-A) is isolated according to known methods, for example by extraction of the compound of formula (I-A) using a suitably selected organic solvent, such as ethyl acetate and the like, followed by removal of the solvent by evaporation. Alternatively, the compound of formula (I-a) is further extracted with NaOH solution and the resulting mixture is acidified, preferably to a pH in the range of about 5 to about 7, to produce a precipitate of the compound of formula (I-a). Preferably, the compound of formula (I-a) is purified according to known methods, for example, by recrystallization from a suitably selected organic solvent or a mixture thereof (e.g. toluene).

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I-S), as described in more detail in scheme 2 below:

scheme 2

A compound of formula (X-S) wherein Q is appropriately substituted according to the above figure¹Is a trifluoromethanesulfonic group, a known compound or a compound prepared by known methods) with an appropriately substituted compound of formula (XI-S) in which PG is¹Hydrogen or a suitably selected nitrogen protecting group, e.g. Boc, Cbz, etc., preferably Boc; and wherein M¹Hydrogen) in the presence of a base, examples of bases are: such as K₂CO₃、Na、Cs₂CO₃Etc. (preferably K)₂CO₃) An inorganic base of (a); or tertiary ammonium bases such as NMM, TEA, DIPEA, pyridine, and the like; wherein the base is preferably present in an amount ranging from about 1.0 to about 5.0 molar equivalents, preferably from about 4.0 to 5.0 molar equivalents; the reaction is carried out in an organic solvent such as toluene, acetone, DMF and the like, preferably in a polar aprotic solvent, such as acetone, DMF, 2-butanol and the like, preferably acetone; provided that the compounds of formula (X-S) and the compounds of formula (XI-S) are soluble in the selected organic solvent; the reaction produces the corresponding compound of formula (XII-S).

Alternatively, a compound of formula (X-S) (wherein Q¹Is trifluoromethanesulfonic group) with an appropriately substituted compound of formula (XI-S) (wherein PG is¹Is a nitrogen protecting group such as Boc, Cbz, etc., preferably BOC; and wherein M¹Is a metal cation, e.g. sodium cation (Na)⁺) Potassium cation (K)⁺) Etc.; or a tertiary ammonium cation, such as an N-methylmorpholine cation, a trialkylammonium cation (e.g., triethylammonium cation), etc., preferably an N-methylmorpholine cation) in an organic solvent such as toluene, acetone, DMF, etc.; preferably in a polar aprotic solvent, such as acetone, DMF, 2-butanol, and the like, preferably acetone; provided that the compounds of formula (X-S) and the compounds of formula (XI-S) are soluble in the selected organic solvent; the reaction produces the corresponding compound of formula (XII-S).

Deprotection of a compound of formula (XII-S) according to known methods yields the corresponding formula (I-S)The compound of (1). For example, PG in which a compound of formula (XII-S)¹In the case of BOC, the compound of formula (XII-S) is reacted with an appropriately selected acid (e.g., HCl (e.g., aqueous HCl), TFA, etc.) in an organic solvent (e.g., methanol, ethanol, IPA, etc.) to deprotect the compound of formula (XII-S) to produce the corresponding compound of formula (I-S).

Preferably, the compound of formula (I-S) is isolated according to known methods, for example by extraction of the compound of formula (I-S) using a suitably selected organic solvent, such as ethyl acetate and the like, followed by removal of the solvent by evaporation. Alternatively, the compound of formula (I-S) is further extracted with NaOH solution and the resulting mixture is acidified, preferably to a pH in the range of about 5 to about 7, to produce a precipitate of the compound of formula (I-S). Preferably, the compounds of formula (I-S) are purified according to known methods, for example, by recrystallization from a suitably selected organic solvent or a mixture thereof, such as toluene.

The invention also includes pharmaceutical compositions comprising one or more compounds prepared according to any of the methods described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compounds with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations (e.g., suspensions, elixirs and solutions), suitable carriers and additives include water, glycols, oils, monohydric alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like. For solid oral preparations (e.g., powders, capsules, tablets), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also be coated with substances such as sugars or with an enteric coating to regulate the primary site of absorption. For parenteral administration, the carrier will usually consist of sterile water, and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared using aqueous carriers along with suitable additives.

To prepare the pharmaceutical compositions of the present invention, one or more of the compositions of the present invention as the active ingredient are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of administration of the preparation desired, e.g. oral or parenteral such as intramuscular injection. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations (e.g., suspensions, elixirs and solutions), suitable carriers and additives include water, glycols, oils, monohydric alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations (e.g., powders, capsules, caplets, and tablets), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. Tablets may be sugar-coated or enteric-coated, if desired, by standard techniques. For parenteral dosage forms, the carrier will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid solubility or preservation. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) the amount of active ingredient required to deliver the effective dose as described above. The pharmaceutical compositions herein will contain about 0.01 to 10,000mg per metered unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoon, etc.) or any range therein, and may be administered in a dosage of about 0.01 to 500 mg/kg/day, or any range therein, preferably about 1.0 to 50 mg/kg/day, or any range therein. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the compound employed. Daily administration or post-cycle administration (post-periodic dosing) may be employed.

Preferably, these compositions are in unit dosage forms, such as tablets, pills, capsules, powders, granules, parenteral sterile solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for parenteral oral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be formulated for once weekly or monthly administration. For example, insoluble salts of the active compounds (e.g., caprate) can provide long acting formulations for intramuscular injection. To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier, such as conventional tableting ingredients, for example corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutically acceptable diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500mg of the active ingredient of the present invention. Tablets or pills of the new composition may be coated or compounded to provide a dosage form that provides long-lasting benefits. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating covering the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby allowing the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid formulations which may be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (cottonseed, sesame, coconut or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for use in aqueous suspensions include synthetic or natural gums (e.g. tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The methods of treatment of epilepsy and related disorders described herein may also be performed with a pharmaceutical composition comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01mg and 1000mg or any range therein of the compound. The compound is preferably present in an amount of about 10 to 500mg and may be formulated into any suitable dosage form depending on the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coating materials. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release), granules and powders; and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, the compounds of the present invention may be administered by topical intranasal administration using suitable intranasal vehicles, or via transdermal patches well known to those skilled in the art. When administered in the form of a transdermal delivery system, administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, and the like). Moreover, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable disintegrants include, but are not limited to, starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The liquid forms may include suspending or dispersing agents, such as natural and synthetic gums, suitably flavored, such as tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

To prepare the pharmaceutical compositions of the present invention, the compound of formula (I) is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral. Suitable pharmaceutical carriers are well known in the art. A description of certain such pharmaceutical carriers is published in the American society for pharmacy and the British society for pharmacyThe Handbook of Pharmaceutical Excipients(handbook of pharmaceutical adjuvants).

Methods of formulating pharmaceutical compositions are described in various publications, for examplePharmaceutical Dosage Forms：Tablets，Second Edition，Revised and ExpandedVolumes 1-3, edited by Lieberman et al (Tablets of pharmaceutical dosage forms (second revised enhancement), Vol.1-3, edited by Lieberman et al);Pharmaceutical Dosage Forms：Parenteral Medicationsvolumes1-2, edited by Avis et al (parenteral drugs of pharmaceutical dosage forms, Vol.1-2, edited by Avis et al); andPharmaceutical Dosage Forms：Disperse Systemsvolumes1-2, edited by Lieberman et al (dispersions of pharmaceutical dosage forms, Vol. 1-2, edited by Lieberman et al); the above publication is published by Marcel Dekker, inc.

The compounds of the present invention may be administered in any of the above compositions and according to art-established dosing regimens, as long as the treatment of epilepsy or related disorders is desired.

The daily dosage of the product prepared according to any of the methods described herein may vary over a wide range of from 0.01 to 10,000mg per adult human per day, or any range therein. For oral administration, the compositions are preferably in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500mg of the active ingredient, the dosages being adjusted according to the condition of the patient to be treated. An effective amount of the drug is typically administered at a dosage level of about 0.01mg to about 500mg, or any range therein, per kilogram of body weight per day. Preferably, the range is from about 0.5 to about 250mg per kilogram body weight per day, or any range therein. More preferably, the range is from about 1.0 to about 100mg per kilogram of body weight per day, or any range therein. More preferably, the range is from about 1.0 to about 50mg per kilogram of body weight per day, or any range therein. The compounds may be administered on a regimen of 1-4 times daily.

The optimal dosage to be administered can be determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease. In addition, factors related to the particular patient being treated (including patient age, weight, diet, and time of administration) can also affect dose adjustments.

One skilled in the art will recognize that both in vivo and in vitro assays are predictive of the ability of a test compound to treat or prevent a given disease using appropriate, known and generally accepted cellular and/or animal models.

Those skilled in the art will also recognize that human clinical trials (including human first use, dose discovery, and efficacy trials in healthy patients and/or patients with a given disease) can be accomplished according to methods well known in the clinical and medical arts.

The following examples are presented to aid in the understanding of the present invention, but are not intended to, and should not be construed to, limit the claims of the invention following the examples in any way.

In the following examples, some of the synthetic products that have been isolated as residues are listed. It will be understood by those skilled in the art that "residue" does not limit the physical state of the product as it is isolated and may include, for example, solids, oils, foams, gums, slurries, and the like. All melting points were determined by TA-Q100 Differential Scanning Calorimetry (DSC).

Example 1: tert-butylsulfamoylcarbamate (Boc-sulfonamide)

Tert-butylsulfamoylcarbamate (Boc-sulfonamide) was prepared according to the procedure of Masui et al (Masui, T; Kabaki, M.; Watanabe, H.; Kobayashi, T.; Masui, Y., Org. ProcesssRev. 2004, 8, 408-410(Masui, T., Kabaki, M., Watanabe, H., Kobayashi, T.; Masui, Y., "organic Process research and development, 2004, Vol. 8, 408-410 page)).

Example 2: tert-Butylsulfamoylcarbamic acid sodium salt

Tert-butylsulfamoylcarbamate (6.0g, 30.58mmol), methanol (50mL) and sodium hydroxide (2.45g, 30.63mmol) were mixed together in a 100mL round-bottomed flask. After stirring for a few minutes, the solvent was distilled off under reduced pressure to give a white solid. The solid was dissolved in methanol (50mL) by heating. The obtained mixture is subjected toHot filtration to remove some fine insoluble solids to give a clear solution. The solvent was removed by evaporation and the remaining solid product was recrystallized in EtOAc/MeOH. The resulting crystalline solid was collected by filtration, air-dried,the title compound is obtained.

Melting point: 224 deg.C

¹H NMR(d₆-DMSO)：d5.19(s，2H)，1.31(s，9H)

Example 3: n-methylmorpholine tert-butylsulfamoylcarbamate

tert-Butylsulfamoylcarbamic acid (6g, 30.58mmol) was mixed together with methanol (50mL) and N-methylmorpholine (6.19g, 6.75mL, 61.15mmol) in a 100mL round-bottom flask. The resulting mixture was stirred at room temperature for about 10-15 minutes. Distilling at 30 deg.C under reduced pressure to remove most of solvent, and obtaining a final volume of about 10-15mL after distillation. The resulting solution was diluted with ethyl acetate (about 40mL), evaporated to a final volume of about 15mL to remove most of the solvent, and then allowed to stand at room temperature. The product began to precipitate as a crystalline white solid. Heptane was added slowly to ensure maximum precipitation. The solid was collected by filtration, washed with heptane containing 2-3% EtOAc, and then air dried to give the title compound.

Melting point: 100 deg.C

¹H NMR(d₆-DMSO)：d10.78(bs，1H)，7.23(s，2H)，3.56(t，J＝4.6Hz，4H)，2.33-2.26(m，4H)，2.16(s，3H)，1.43(s，9H)

Elemental analysis: c₁₀H₂₃N₃O₅The calculated value of S is: c, 40.39; h, 7.80; n, 14.13; s, 10.78. The measured values are: c, 39.88, H, 7.97, N, 14.08, S, 10.85.

Example 4: (R) - (6-chloro-2, 3-dihydrobenzo [ b ]][1，4]Dioxacyclohex-2-yl) methyltrifluoromethane Sulfonic acid group

Reacting (S) - (6-chloro-2, 3-dihydrobenzo [ b ]][1，4]Dioxacyclohex-2-yl) methanol (2g, 10mmol) was mixed together with toluene (25mL) and pyridine (2.18mL, 27mmol) in a 300mL three-necked flask. The resulting mixture was cooled to 0 ℃. To the resulting mixture was added slowly trifluoromethanesulfonic anhydride (2.18mL, 12.96mmol) with the internal temperature kept below 10 ℃. After the addition was complete, the resulting mixture was stirred for 0.5 hours. The progress of the reaction was monitored by TLC analysis on silica gel plates with EtOAc/heptane (1: 1) as eluent. The resulting mixture was washed with NaHCO₃The aqueous solution is quenched at 0 ℃. The organic layer was separated, washed successively with 0.1N HCl and aqueous sodium bicarbonate solution and then MgSO₄And (5) drying. The resulting solution was stirred with a small amount of silica gel, filtered and concentrated under reduced pressure to give a colorless oil. The oil was placed under high vacuum until the weight was constant to give the title compound.

¹H NMR(CDCl₃)：d6.93-6.91(m，1H)，6.86(d，J＝1.9Hz，2H)，4.67(d，J＝5.1Hz，2H)，4.57-4.49(m，1H)，4.32(dd，J₁＝2.4，J ₂＝11.7Hz，1H)，4.13(dd，J₁＝6.1，J ₂＝11.7Hz，1H).

Example 5: n- [ [ (2S) -6-chloro-2, 3-dihydro- [1, 4 [ ]]-benzodioxan-2-yl]Methyl radical]Sulphur Amides of carboxylic acids

Step A: (S) -tert-butyl (6-chloro-2, 3-dihydrobenzo [ b ]][1，4]Dioxane-2-yl) methyl (sulfamoyl) carbamic acid ester

(R) - (6-chloro-2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyltrifluoromethanesulfonic acid group (3g, 9.0mmol), Boc-sulfonamide (1.95g, 10mmol), and acetone (45mL) were placed in a 300mL round bottom flask equipped with a nitrogen inlet and a magnetic stir bar. To the resulting mixture was added potassium carbonate (5g, 36mmol), and stirred for 0.75 hours. The progress of the reaction was monitored by TLC analysis on silica gel plates with EtOAc/heptane (1: 1) as eluent. The resulting mixture was filtered to remove the solid carbonate, and the filtrate was evaporated under reduced pressure to give (S) -tert-butyl (6-chloro-2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl (sulfamoyl) carbamate as an oily residue which solidified upon standing at room temperature for 24 hours.

¹H NMR(d₆-DMSO)：d7.61(s，2H)，6.99(d，J＝1.6Hz，1H)，6.94-6.86(m，2H)，4.49-4.39(m，1H)，4.25(dd，J₁＝2.3，J₂＝11.9Hz，1H)，4.07(dd，J₁＝5.5，J ₂＝11.9Hz，1H)，3.92(dd，J₁＝7.0，J ₂＝14.9Hz，1H)，3.79(dd，J₁＝5.5，J₂＝14.9Hz，1H)，1.40(s，9H)。

And B: n- [ [ (2S) -6-chloro-2, 3-dihydro- [1, 4 [ ]]-benzodioxan-2-yl]Methyl radical]Sulphur Amides of carboxylic acids

The product from step A was treated with 4M HCl in dioxane (30mL) and stirred for 3.5 hours. The progress of the reaction was monitored by TLC analysis on silica gel plates with EtOAc/heptane (1: 1) as eluent. The resulting mixture was added to ice water, quenched, and the product was extracted with EtOAc. The organic layer was washed with aqueous sodium bicarbonate solution and then anhydrous MgSO₄Drying, filtering and concentrating under reduced pressure to obtain a light pink oil. The oil was dissolved in hot toluene (10mL), treated with a small amount of silica gel to remove the color, and then filtered while hot. The filtrate was left standing at normal temperature. The resulting crystalline solid was collected by filtration, washed with a 1: 1 toluene/heptane mixture and air dried to give the title compound.

Melting point: 101.7 deg.C

Example 6: n- [ [ (2S) -6-chloro-2, 3-dihydro-1, 4-benzodioxan-2-yl]Methyl radical]Sulfonyl radical Amines as pesticides

Reacting (R) - (6-chloro-2, 3-dihydrobenzo [ b ]][1，4]Dioxiren-2-yl) methyltrifluoromethanesulfonic acid (1.5g, 4.51mmol) and dimethylformamide (25mL) were placed in a 100mL round bottom flask equipped with a nitrogen inlet and a magnetic stir bar. Boc-sulfonamide sodium salt (1.08g, 4.96mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC analysis on silica gel plates with EtOAc/heptane (1: 1) as eluent. At the end of the reaction, concentrated aqueous HCl (22mL) was added and the resulting mixture was stirred for 3 hours until TLC analysis indicated complete conversion. The resulting mixture was diluted with ice water (100mL) and the product was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate and with anhydrous Na₂SO₄And (5) drying. Filtering the obtained solution, and concentrating under reduced pressure to obtain clear oily substance; the oil was dissolved in toluene (5mL) and left to stand at room temperature to give a white solid precipitate. The solid was collected by filtration and air dried to give the title compound. The recovered product was obtained from the filtrate.

Alternative workup may also be used to prepare a single batch of the title compound. Alternative follow-up operations are as follows: the product was extracted with EtOAc and the EtOAc layer was extracted with 1N NaOH as described above. The aqueous layer was washed with EtOAc, cooled to a temperature between about 5-10 ℃ and then acidified to pH 5-7 with 1N HCl to produce a precipitate. The precipitate was collected by filtration to give the title compound as a white solid.

Example 7

As a specific example of an oral composition, 100mg of the compound prepared in example 5 or example 6 is formulated with lactose fine enough to provide a total amount of 580 to 590mg to fill an O-type hard capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, modifications and/or adaptations of the invention within the scope of the following claims and their equivalents.

Claims (27)

1. A process for the preparation of a compound of formula (I-a) or a pharmaceutically acceptable salt thereof;

wherein

R¹And R²Each independently selected from hydrogen and lower alkyl;

a is an integer of 1 to 2;

is selected from

Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; and wherein each R⁵Are each independently selected from halogen, lower alkyl and nitro;

provided that when

Is composed of

When the temperature of the water is higher than the set temperature,

a is 1;

the method comprises the following steps:

reacting a compound of formula (X) (wherein Q)¹Is trifluoromethanesulfonic acid group) with a compound of formula (XI) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Hydrogen) in an organic solvent in the presence of a base to produce the corresponding compound of formula (XII);

deprotecting said compound of formula (XI I) to produce said corresponding compound of formula (I-A).

2. The method of claim 1, wherein PG¹Is Boc, and wherein M¹Is hydrogen.

3. The process of claim 1, wherein the base is an inorganic base.

4. The method of claim 1, wherein the base is K₂CO₃And is present in an amount ranging from about 1.0 to about 5.0 molar equivalents.

5. The method of claim 1, wherein the organic solvent is acetone.

6. A process for the preparation of a compound of formula (I-a) or a pharmaceutically acceptable salt thereof;

wherein

R¹And R²Each independently selected from hydrogen and lower alkyl;

a is an integer of 1 to 2;

is selected from

Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; and wherein each R⁵Are each independently selected from halogen, lower alkyl and nitro;

provided that when

Is composed of

If so, a is 1;

the method comprises the following steps:

reacting a compound of formula (X) (wherein Q)¹Is trifluoromethanesulfonic acid group) with a compound of formula (XI) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Is a metal cation or a tertiary ammonium cation) in an organic solvent to produce said corresponding compound of formula (XII);

deprotecting the compound of formula (XII) to produce the corresponding compound of formula (I-A).

7. The method of claim 6, wherein PG¹Is BOC, and wherein M¹Is N-methylmorpholine cation.

8. The method of claim 6, wherein the organic solvent is DMF.

9. A process for the preparation of a compound of formula (I-S) or a pharmaceutically acceptable salt thereof;

the method comprises the following steps:

reacting a compound of formula (X-S) (wherein Q)¹Is trifluoromethanesulfonic group) with a compound of formula (XI-S) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Hydrogen) in an organic solvent in the presence of a base to produce the corresponding compound of formula (XII-S);

deprotecting the compound of formula (XII-S) to produce the corresponding compound of formula (I-S).

10. The method of claim 9, wherein PG is¹Is BOC.

11. The method of claim 9, wherein M¹Is hydrogen.

12. The process of claim 9, wherein the base is an inorganic base.

13. The process of claim 12, wherein the inorganic base is K₂CO₃。

14. The method of claim 9, wherein the base is present in an amount ranging from about 1.0 to about 5.0 molar equivalents.

15. The process of claim 14 and wherein the base is present in an amount ranging from about 4.0 to about 5.0 molar equivalents.

16. The method of claim 9, wherein the organic solvent is acetone.

17. A process for the preparation of a compound of formula (I-S) or a pharmaceutically acceptable salt thereof;

the method comprises the following steps:

reacting a compound of formula (X-S) (wherein Q)¹Is trifluoromethanesulfonic group) with a compound of formula (XI-S) (wherein PG is¹Is a nitrogen protecting group, and wherein M¹Is a metal cation or a tertiary ammonium cation) in an organic solvent to produce said corresponding compound of formula (XII-S);

deprotecting the compound of formula (XII-S) to produce the corresponding compound of formula (I-S).

18. The method of claim 17, wherein PG is¹Is BOC.

19. The method of claim 17, wherein M¹Is a tertiary ammonium cation.

20. The method of claim 17, wherein M¹Is N-methylmorpholine cation.

21. The method of claim 17, wherein the organic solvent is DMF.

22. A compound of the formula (XII),

wherein

PG¹Is hydrogen or a nitrogen protecting group (preferably, PG)¹Is tert-butyloxycarbonyl)

R¹And R²Each independently selected from hydrogen and lower alkyl;

a is an integer of 1 to 2;

is selected from

Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; and wherein each R⁵Are each independently selected from halogen, lower alkyl and nitro;

provided that when

Is composed of

When the value is 1, a is obtained.

23. The compound of claim 22, wherein PG¹Selected from hydrogen, Boc and Cbz.

24. The compound of claim 22, wherein PG¹Is tert-butyloxycarbonyl.

25. A compound of formula (XII-S),

wherein

PG¹Is hydrogen or a nitrogen protecting group.

26. The compound of claim 25, wherein PG is¹Selected from hydrogen, Boc and Cbz.

27. The compound of claim 25, wherein PG is¹Is tert-butyloxycarbonyl.